1. Field of the Invention
The invention relates to the field of anti-inflammatory drugs. More specifically, the invention relates to the use of compounds of formula (1) for the treatment and prevention of conditions related to inflammations, such as inflammatory joint diseases, and other diseases where inflammatory conditions are the underlying cause, and to methods for their preparation, medicaments comprising these compounds, and their use for the treatment of humans and animals.
2. Background and Description of Related Art
According to the Centers for Disease Control and Prevention, National Institute of Arthritis and Musculoskeletal and Skin Diseases, more than 40 million people in the US have some form of arthritis (one in every six people). It is estimated that by the year 2020, 59 million people in the United States will have arthritis. Rheumatic diseases are the leading cause of disability among persons age 65 and older. Approximately 20.7 million adults in the United States have the most common form of arthritis, osteoarthritis, also called degenerative joint disease. Most persons over the age of 75 are affected with osteoarthritis in at least one joint, making this condition a leading cause of disability in the US. Rheumatoid arthritis, the most crippling form of arthritis, affects approximately 2.1 million Americans and two to three times more women than men. The average onset for rheumatoid arthritis is between the ages of 20 and 45 years.
Since non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed by physicians and widely used by arthritis patients and those suffering from inflammation-related diseases, researchers and drug manufacturers team up to develop newer, safer, more effective choices. In accordance with this trend, the embodiment relates to new compounds of formula (1) that exhibit anti-inflammatory activity commonly observed among the members of the NSAID category of drugs. A compound of formula (1) is extremely effective in reducing and preventing inflammation and hence widens the treatment choices for the physician and the patient.
Certain prostaglandins are mediators of inflammations but are also implicated in areas other than inflammation-related conditions, such as cancer progression. In view of their effect on mitogenesis, cellular adhesion and apoptosis, prostaglandins play a major role in several types of cancers where an important cycloogygenase-2 (COX-2) expression has been demonstrated (Julémont, F., et al., J Med Chem 2004, 47, 6749). The different roles of lipoxygenases (LOXs) and their metabolic products in carcinogenesis and chemoprevention have been studied (Pommery, N., et al., J Med Chem 2004, 47, 6195). As examples, the effect of the 5-LOX/COX-2 inhibitor DMDMBF30 showed promise as an inhibitor of the pancreatic cancer cell line Capan2 (Zhang, B. et al., World J Gastroenterol 2008, 14, 2494) and licofelone, a dual COX/5-LOX inhibitor, implemented apoptosis in HCA-7 colon cancer cells (Tavolari, S. et al., Carcinogenesis 2008, 29, 371). Celecoxib, a popular NSAID and a specific COX-2 inhibitor, was implicated in the inhibition of some nonmelanoma skin cancers (Elmets, C. A., J Natl Cancer Inst 2010, 102 (issue 24). Since NSAIDs inhibit COX-2/LOX in various ratios and degrees of efficiency, they can play a role in cancer prevention although COX-2 inhibition and anti-cancer effect may not be in direct correlation. Celecoxib, for example, was shown to induce apoptosis in prostate cancer cells but this effect was independent of the COX-2 inhibitory activity (Song, X., et al., J Natl Cancer Inst 2002, 94, 585).
The transcription factor NF-κB, the selective name for dimeric transcriptional modulators comprising the Rel family of proteins, has also been recognized to play a significant role in mediating inflammatory events through its ability to induce transcription of pro-inflammatory genes (Plummer S. M., et al., Oncogene, 1999, 18, 6013). Among the products, COX-2 and iNOS, the inducible isoform of nitric oxide synthase, are prime examples of enzymes that can change cell function, including the generation of inflammatory responses. iNOS is involved in immune responses and produces NO as a defense mechanism. It is the proximate cause of septic shock and may play a role in many diseases with an autoimmune etiology.
It has been shown that NF-κB is critical for the induction of COX-2 gene expression by TNFα in human colon tumor cells (Morteau, J. O., et al., Immunology 1998, 95, 537). Overexpression of COX-2 in colon epithelial cells, which occurs during colon carcinogenesis, causes resistance to apoptosis, suggesting that inhibition of NF-κB might reinstate susceptibility to apoptosis (Tsujii, M. and Dubois, R. N., Cell 1995, 83, 493). The ability to inhibit the NIK/IKK signaling complex, and hence preventing the activation of NF-κB, may be common to the action of some anti-inflammatory and chemopreventive agents. Aspirin and salicylates, known to inhibit phosphorylation and degradation of the IκB kinase enzyme complex (Kopp, E. and Ghosh, S., Science 1994, 265, 956), have been shown to inhibit the phosphorylation of IκB by specifically reducing ATP binding to IKKb (Yin, M. J, et al., Nature 1998, 396, 77) thus preventing the activation of NF-κB and potentially increasing chemosensitivity in many cancers (McCarty, M. F., Block, K. I., Integr Cancer Ther. 2006, 5, 252-268). The extensive involvement of Rel/NF-kB transcription factors in human inflammation and disease has established them as targets for therapeutics.
Many naturally occurring substances have anti-inflammatory activity and also exhibit chemopreventive effects on tumors. As per example, dietary flaxseed apparently prevents colon tumor development (Bommareddy, A., et al., Nutr Cancer 2006, 54, 216) and Boswellia serrata and ginger root extracts were used in the ancient Indian tradition of Ayervedic Medicine to control inflammation. The extract of Boswellia serrata was claimed to be superior to Valdecoxib in terms of safety, efficacy and duration of action (Sontakke, S., et al., Indian J Pharmacol 2007, 38, 27). Bromelain, derived from pineapples, is used to reduce post-operative swelling. Quercitin occurs naturally in many plants, most notably in red grapes, green tea, and onions and is used against a number of ailments wherein inflammation may be the underlying cause. Similarly, curcumin, the yellow pigment from turmeric, possesses anti-inflammatory and anti-oxidant activity (Ammon, H. R. T., et al., Planta Med 1991, 57, 1-7). It is also known as an anticarcinogenic agent and was studied extensively. It inhibits activation of NF-κB via the NIK/IKK signalling complex and thus exerts its activity by blocking many adverse reactions in which NF-κB plays a major role (U.S. Pat. No. 5,891,924, 1999). The hallmarks of these compounds are good anti-inflammatory activities, lack of stomach irritation and ulceration (Etzel R., Phytomed 1996, 3, 91) but only moderate inhibitory activities against isolated cycloogygenases.
Similar to these naturally occurring substances, compounds of formula (1) are also relatively weak inhibitors of isolated COX-1, COX-2, and 5-LOX enzymes. The apparent absence of gastrointestinal liabilities, their potent anti-inflammatory activity in vivo, as demonstrated by the adjuvant-induced arthritis test in rats, and their relatively weak activity in COX-specific in vivo tests, suggest a mode of action that differs from typical NSAIDs but resembles that of naturally occurring anti-inflammatory agents. A compound of the formula (1) is thus expected to be generally free of gastrointestinal disturbances and cardiovascular liabilities and to exhibit, in addition to anti-inflammatory action, chemopreventive activities in oncology, asthma, neurodegenerative diseases and heart diseases.
3. Prior Art
The object compounds of this embodiment are novel in a chemical and unusual in a pharmacological sense as they exert their biological function by a mechanism that is uncharacteristic of typical NASIDs.